PhD ceremony Ms. U.M. Domanska: Tumor microenvironment: preclinical insights into therapy resistance and targeting strategies
|When:||Mo 09-12-2013 at 09:00|
|Where:||Academiegebouw, Broerstraat 5, Groningen|
PhD ceremony: Ms. U.M. Domanska
Dissertation: Tumor microenvironment: preclinical insights into therapy resistance and targeting strategies
Promotor(s): prof. E.G.E. de Vries
Faculty: Medical Sciences
Activation of treatment resistance mechanisms in cancer are a major hurdle in developing an ultimately successful treatment. A body of preclinical research indicates that tumour adaptation to therapy is largely influenced by changes in the tumour microenvironment. In this thesis, two cell-surface receptors mediating interactions of cancer cell with its microenvironment - chemokine receptor 4 (CXCR4) and formylated-peptide receptor 1 (FPR1) - were studied. Both receptors may be overexpressed on cancer cells and primarily mediate their migration. The aim was to gain a better understanding of the role of CXCR4 and FPR1 in the biology of solid cancers, with a particular focus on the role of CXCR4 in the interactions of tumour cells with stromal microenvironment and its influence on the anti-cancer therapy response. Preclinical studies described in this thesis reveal the contribution of CXCR4/CXCL12 signaling to the microenvironment-mediated resistance of solid tumour cells to classical therapies. Up-regulated by anti-cancer treatment, involved in tumour resistance, survival, metastasis and vascularization, this chemokine receptor/ligand pair may be a valuable target for therapy of solid tumours. In addition, FPR1 receptor is investigated as an important inducer of migration of high-grade brain tumour cells. The effects of the recently identified FPR1 ligands, present in the necrotic tumour microenvironment, and the potent inhibitory effects of the FPR1 antagonist, are shown in preclinical models of high-grade glioma. These step-by-step advances in understanding the functions and dynamics of G protein-coupled receptors in tumour microenvironment should help to define novel, rational strategies for more successful cancer treatment.